New study begins to uncover the skeletal basis of variation in height

A new study has delved deeper than ever before into understanding the genetic basis of adult human height. The study is
the first of its kind, using exploratory statistical analyses to uncover how 17 genetic variants that are implicated in
human height affect the length of particular skeletal components of the body, used as a proxy for height subcomponents.

The research opens the door to a better understanding of the developmental pathways that contribute to human height.
Four of the variants that the team described as associated with height had not previously been identified.

Researchers at the Wellcome Trust Sanger Institute led an international consortium of investigators from Canada,
Israel, the Netherlands and UK to study approximately 20,000 individuals, searching for regions in the genome that were
associated with differences in height. By looking through 300,000 known SNPs - single letter changes in genetic code -
the team found 17 regions that contributed to human height. To understand better how variation at these regions
contributed to height, the team took skeletal measurements of the spine, leg and hip-axis, to determine the specific
effects of these genetic markers on the length of skeletal size measurements.

"The statistical analysis of height subcomponents poses challenges due to the high correlation
among the different traits," explains Dr Nicole Soranzo, Sanger Institute researcher and lead author on the
study. "There have been a handful of genome-wide association studies that have concentrated on
height in the past, but the impact of variants on the different skeletal subcomponents of height has never been
investigated. The study begins to clear a path for research that goes beyond looking at associations, to look at
biological processes involved in differential height components."

" The study begins to clear a path for research that goes beyond looking at associations, to look at biological
processes involved in differential height components "

Dr Nicole Soranzo

Genetic regions that play a role in increased human height have, in the past, been uncovered in genome-wide association
studies. Height is relatively easy to measure simply and accurately. However, to look at the contribution of individual
skeletal components is considerably more complicated.

"Overall height can mask differences in the skeletal components: researchers need to tease apart
the contribution of genetic loci to each of these components. Our study is a first attempt towards this goal but much
larger samples will be needed to accomplish it," explains Dr Panos Deloukas, senior investigator at the Sanger
Institute and coordinator of the consortium. "The final upper or lower body size of humans might be
the result of independent growth pathways that need to be understood."

The team wanted to elucidate how the 17 variants strongly associated with adult height impacted on the length of
individual skeletal components. To measure the length of the skeletal components the team used data from
high-resolution densitometric scans of human bones. Nine of the variants were associated with increased trunk length;
approximately 5% of the variance in femur length was explained by a combination of all of the variants. Seven of the
variants influenced hip-axis length, which is a known predictor for osteoporosis in humans.

The height of an individual is composite of many genetic influences and each genetic region identified so far adds less
than half a centimetre to the height of the individual carrying the underlying variant. In total the 17 regions,
reported in this study, account for approximately 2-3% of the variance in height of the sample. The four novel height
loci discovered bring the total number of genes implicated in human height to 47. These genes appear to be involved in
a variety of processes: from DNA replication to intercellular signalling, cell division and skeletal development.

"The array of gene functions underlying the determination of human height are already starting to
show links to several human diseases," says Dr Fernando Rivadeneira, Assistant Professor at the Erasmus MC and
co-lead author on the study. "For instance, our current finding on GDF5 - one of the genes
associated with hip-axis length - provides further understanding to our previous finding, where we found GDF5
associated with osteoarthritis and bone fracture susceptibility. Similarly, many other height loci with demonstrated
overgrowth functions have a known role in human cancers. In-depth analysis of the way in which common variants in genes
have modest effects on people's height can provide important insights into understanding the causes of human
diseases."

As well as developing new methodological principles for study in this area, the researchers' findings could lead to the
discovery of medically important genetic regions for several human diseases. More research and replication using larger
samples will strengthen the results and might lead to a more developed understanding of clinical effects.

"This exciting area of research is ripe for further investigation," explains Professor Tim
Spector, Director of the TwinsUK project at Kings College London. "We are beginning to understand
the genetic basis, not just of human height, but of how individual bones develop. This research underscores the
importance of using highly characterised human populations and will help understand musculoskeletal disease in
humans."

Division of Community Health Sciences, St George's, University of London, London, UK

Department of Twin Research and Genetic Epidemiology

The Department of Twin Research and Genetic Epidemiology (DTR) encompasses the biggest UK adult twin registry of
11,000 twins used to study the genetic and environmental aetiology of age related complex traits and diseases. The DTR
has been one of the major departments of King's College London Division of Genetics and Molecular Medicine since 2006
with a team of over 40 staff.

Erasmus Medical Center

The Erasmus Medical Center is an academic medical centre in which new knowledge is being developed and passed on to
future professionals. This knowledge covers a broad field of interests that stretches from illness to health, and from
individual to community healthcare. Erasmus Medical Center is the Netherlands' largest academic medical centre. As such
it is able to provide special opportunities for education, research, and patient care in this country. Erasmus MC is an
innovative centre for high-quality knowledge development, training, and care in the fields of illness and health.

Websites

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

Websites

The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.